Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):26-37. doi: 10.1016/j.bbadis.2018.10.017. Epub 2018 Oct 13.


Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism.

Keywords: EBP50; Invadopodia; Invasion; Mesenchymal-vasculogenic transition; Metastases; SLC9A3R1; Vasculogenic mimicry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mutant Proteins / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Phenotype*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Signal Transduction
  • Sodium-Hydrogen Exchanger 1 / metabolism
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • Xenograft Model Antitumor Assays
  • Zebrafish


  • Mutant Proteins
  • Phosphoproteins
  • Slc9a1 protein, mouse
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor